WO2012021712A1 - Analogues de tétracycline - Google Patents

Analogues de tétracycline Download PDF

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Publication number
WO2012021712A1
WO2012021712A1 PCT/US2011/047428 US2011047428W WO2012021712A1 WO 2012021712 A1 WO2012021712 A1 WO 2012021712A1 US 2011047428 W US2011047428 W US 2011047428W WO 2012021712 A1 WO2012021712 A1 WO 2012021712A1
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WIPO (PCT)
Prior art keywords
alkyl
infection
alkylene
carbocyclyl
mmol
Prior art date
Application number
PCT/US2011/047428
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English (en)
Inventor
Chi-Li Chen
Roger B. Clark
Yonghong Deng
Louis Plamondon
Cuixiang Sun
Xiao-Yi Xiao
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Tetraphase Pharmaceuticals, Inc.
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Application filed by Tetraphase Pharmaceuticals, Inc. filed Critical Tetraphase Pharmaceuticals, Inc.
Publication of WO2012021712A1 publication Critical patent/WO2012021712A1/fr

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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/36—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/60—1,4-Diazines; Hydrogenated 1,4-diazines
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/84—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms six-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • C—CHEMISTRY; METALLURGY
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    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/20—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/38—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/04—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with only hydrogen atoms, halogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
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    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
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    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems

Definitions

  • the tetracyclines are broad spectrum anti-microbial agents that are widely used in human and veterinary medicine.
  • the total production of tetracyclines by fermentation or semi-synthesis is measured in the thousands of metric tons per year.
  • X is selected from hydrogen, bromo, fluoro, chloro, Ci-C 6 alkyl, -0-Ci-C 6 alkyl, C3-C10 carbocyclyl, -O-C3-C10 carbocyclyl, 4-13 membered heterocyclyl, -0-4-13 membered heterocyclyl, -S(0) m -R 2 , -CN, -N(R 2 )(R 3 ), -S(0) m -N(R 2 )(R 3 ), -C(0)-0-R 2 , -C(0)-N(R 2 )(R 3 ), and -NH-C(0)-(Ci-C 6 alkylene)-N(R 2 )(R 3 ), wherein each alkyl, or alkylene in the group represented by X is optionally substituted with one or more fluoro; and
  • Ring E is selected from C 3 -C 10 carbocyclyl and a (4-13 membered) heterocyclyl,
  • W is selected from C(R 6 ), C(R 6 ) 2 , N, and N(R 7 );
  • Q is selected from C(R 6 ), C(R 6 ) 2 , N, N(R 7 ), O, and S;
  • Y is selected from hydrogen, fluoro, bromo, -CN, -[C(R la )(R lb )] admir-N(R 2 )(R 3 ),
  • each R la and R lb is independently selected from hydrogen, C 1 -C 4 alkyl, and C3-C10 carbocyclyl;
  • R 2 is selected from hydrogen, C -Cn alkyl, -C 0 -C 6 alkylene-C 3 -Ci 0 carbocyclyl, and -Co-C 6 alkylene-4-13 membered heterocyclyl;
  • R 3 is selected from hydrogen, Ci-Cg alkyl, -Co-C 6 alkylene-C3-Cio carbocyclyl, -Co-C 6 alkylene-4-13 membered heterocyclyl, -C(0)-Ci-C 6 alkyl, -C 0 -C 6 -alkylene-C(O)N(R 4 )(R 5 ), -C(0)-C C 6 alkylene-N(R 4 )(R 5 ), -C 2 -C 6 alkylene-N(R 4 )(R 5 ), -S(0) m -Ci-C 6 alkyl, -S(O) m -C 3 -Ci 0 carbocyclyl, and
  • each alkyl, carbocyclyl, alkylene or heterocyclyl in the group represented by R 2 or R 3 is optionally and independently substituted with one or more substituents independently selected from fluoro, chloro, -OH,
  • the 4-7 membered monocyclic heterocylic ring, or the 6-13 membered bicyclic, spirocyclic or bridged heterocyclic ring optionally comprises 1 to 4 additional heteroatoms independently selected from N, S and O;
  • each of R 4 and R 5 is independently selected from hydrogen and C 1 -C4 alkyl; or
  • R 7 is independently selected from hydrogen, -C0-C4 alkylene-C3-Cio carbocyclyl, -C 0 -C 4 alkylene-4-13 membered heterocyclyl, -Ci-C 6 fluoroalkyl, -Ci-C 6 alkyl, -Ci-C 6 hydroxyalkyl, -O-C 3 -C 10 carbocyclyl, -0-4-13 membered heterocyclyl, -C0-C4 alkylene-0-Ci-C4 alkyl, -C0-C4 alkylene-0-Ci-C4 fluoroalkyl, -C(0)-Ci-C 4 alkyl, -C1-C4 alkylene-C(0)-Ci-C 4 alkyl, -C1-C4 alkylene-C(0)-OH, -C(0)N(R 4 )(R 5 ), -N(R 4 )-C(0)-Ci-C 4 alkyl, -C
  • Each m is independently 0, 1 or 2;
  • n 1 or 2;
  • p is 0 or an integer between 1 and 4;
  • Another embodiment of the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound disclosed herein or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition is used in therapy, such as treating an infection in a subject.
  • Another embodiment of the present invention is a method of treating an infection in a subject comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof.
  • Another embodiment of the present invention is the use of a compound disclosed herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating an infection in a subject.
  • Another embodiment of the present invention is the use of a compound disclosed herein or a pharmaceutically acceptable salt thereof for therapy, such as treating an infection in a subject.
  • FIG. 1 is a graph showing post-antibiotic effect of Compound S2-7-5-A against the indicated bacteria.
  • FIG. 2 is a graph showing post-antibiotic effect of Compound S2-7-5-A against the indicated bacteria.
  • FIG. 3 is a graph showing post-antibiotic effect of Compound S2-7-5-A against the indicated bacteria.
  • FIG. 4 is a graph showing post-antibiotic effect of Compound S2-7-5-A against the indicated bacteria.
  • FIG. 5 is a graph showing post-antibiotic effect of Compound S2-7-5-A against the indicated bacteria.
  • FIG. 6 is a graph showing results from the time kill assay using Compound S2-7-5-A against the indicated bacteria.
  • FIG. 7 is a graph showing results from the time kill assay using Compound S2-7-5-A against the indicated bacteria.
  • FIG. 8 is a graph showing results from the time kill assay using Compound
  • FIG. 9 is a graph showing results from the time kill assay using Compound S2-7-5-A against the indicated bacteria.
  • FIG. 10 shows MIC 50 and MIC 90 values for compounds of the invention against a variety of bacteria.
  • FIG. 11 shows the results of a TNT Assay using the referenced compounds.
  • FIG. 12 show the results of using the referenced compound in a Murine Lung Infection Model.
  • FIG. 13 shows the results of using the referenced compound in
  • FIG. 14 is a graph showing results from the time kill assay using the refenced compound against the indicated bacteria.
  • the present invention is directed to a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof.
  • Values and alternative values for the variables in Structural Formula I and for each of the embodiments described herein are provided in the following paragraphs. It is understood that the invention encompasses all combinations of the substituent variables (i.e.; R 1 , R 2 , R 3 , etc.) defined herein.
  • X is selected from hydrogen, bromo, fluoro, chloro, Ci-C 6 alkyl, -0-Ci-C 6 alkyl, C3-C10 carbocyclyl, -O-C3-C10 carbocyclyl, 4-13 membered heterocyclyl, -0-4-13 membered heterocyclyl, -S(0) m -R 2 , -CN, -N(R 2 )(R 3 ), -S(0) m -N(R 2 )(R 3 ), -C(0)-0-R 2 , -C(0)-N(R 2 )(R 3 ), and -NH-C(0)-(Ci-C 6 alkylene)-N(R 2 )(R 3 ), wherein each alkyl, or alkylene in the group represented by X is optionally substituted with one or more fluoro; and each carbocyclyl or heterocyclyl in the group represented by X is optionally substituted with one or more substitutents
  • X is selected from hydrogen, chloro, fluoro, -OCH 3 , -OCF 3 , -OCH 2 F, -N(CH 2 ) 3 and CF 3 .
  • Y is selected from hydrogen, fluoro, bromo, -CN, -[C(R la )(R lb )] admir-N(R 2 )(R 3 ), -N(R 4 )(R 5 ), N0 2 , -NH-C(0)-(Ci-C 4 alkylene)-N(R 4 )(R 5 ), Ci-C 6 alkyl,
  • R la and R lb are independently selected from hydrogen, C 1 -C4 alkyl, and C 3 -C 10 carbocyclyl.
  • Y is hydrogen.
  • Ring E is C 3 -C 10 carbocyclyl or 4-13 membered heterocyclyl. Specifically, Ring E comprises a ring nitrogen atom. Further, Ring E is a non-aromatic ring. Alternatively, Ring E is a 4-7 membered heterocyclyl. More specifically, Ring E is selected from one of the following structures:
  • Ring E is
  • ring E is an optionally substituted aromatic or an optionally
  • X is not hydrogen
  • W is C(R 6 ), C(R 6 ) 2 , N or N(R 7 ). Specifically, W is N or N(R 7 ).
  • Q is C(R 6 ), C(R 6 ) 2 , N, N(R 7 ), O, or S. Specifically, Q is C(R 6 ) 2 .
  • ring E is an optionally substituted aromatic or an optionally substituted heteroaromatic ring
  • X is not hydrogen
  • R 2 is hydrogen, Ci-Ci 2 alkyl, -Co-C 6 alkylene-C3-Cio carbocyclyl, or -Co-C 6 alkylene-(4-13 membered) heterocyclyl.
  • R 3 is hydrogen, Ci-Cg alkyl, -Co-C 6 alkylene-C3-Cio carbocyclyl, -Co-C 6 alkylene-(4-13 membered) heterocyclyl, -C(0)-Ci-C 6 alkyl,
  • each alkyl, carbocyclyl, alkylene or heterocyclyl in the group represented by R 2 or R 3 is optionally and independently substituted with one or more substituents independently selected from fluoro, chloro, -OH, -O-C1-C4 alkyl, C1-C4 alkyl, fluoro-substituted-Ci-C 4 alkyl, -N(R 4 )(R 5 ), C3-C10 carbocyclyl or a (4-13 membered) heterocyclyl.
  • R 2 and R 3 taken together with the nitrogen atom to which they are bound form a 4-7 membered monocyclic heterocylic ring, or a 6-13 membered bicyclic, spirocyclic or bridged heterocylic ring wherein the 4-7 membered monocyclic heterocylic ring, or the 6-13 membered bicyclic, spirocyclic or bridged heterocyclic ring optionally comprises 1 to 4 additional heteroatoms independently selected from N, S and O.
  • R 4 and R 5 is independently hydrogen or C1-C4 alkyl
  • R 6 is independently hydrogen or methyl. Specifically, R 6 is hydrogen.
  • R 7 is independently selected from hydrogen, -C0-C4 alkylene-C3-Cio carbocyclyl, -C0-C4 alkylene-4-13 membered heterocyclyl, -Ci-C 6 fluoroalkyl, -Ci-C 6 alkyl, -Ci-C 6 hydroxyalkyl, -O-C3-C10 carbocyclyl, -0-4-13 membered heterocyclyl, -C0-C4 alkylene-0-Ci-C 4 alkyl, -C0-C4 alkylene-0-Ci-C 4 fluoroalkyl, -C(0)-Ci-C 4 alkyl, -C1-C4 alkylene-C(0)-Ci-C 4 alkyl, -C1-C4 alkylene-C(0)-OH, -C(0)N(R 4 )(R 5 ), -N(R 4 )-C(0)-Ci-C 4 alkyl, -C(0)-(C
  • R 7 is independently hydrogen, -C0-C4 alkylene-C3-Cio carbocyclyl, -C0-C4 alkylene-4-13 membered heterocyclyl, -Ci-C 6 fluoroalkyl, -Ci-C 6 alkyl, -O-C3-C10 carbocyclyl, -0-(4-13 membered) heterocyclyl, -C0-C4 alkylene-0-Ci-C 4 alkyl, -C 0 -C 4 alkylene-0-Ci-C 4 fluoroalkyl, -C(0)-C C 4 alkyl, -C(0)N(R 4 )(R 5 ), -N(R 4 )-C(0)-Ci-C 4 alkyl, or -C 0 -C 4 alkylene-N(R 4 )(R 5 ).
  • R 7 is H, -Ci-C 6 fluoroalkyl, or -Ci-C 6 alkyl. Further, R 7 is -Ci-C 6 fluoroalkyl or -Ci-C 6 alkyl. Further, R 7 is -Ci-C 6 alkyl. R 7 is selected from methyl, ethyl, 2-fluoro-ethyl, propyl, isopropyl, butyl, and pentyl. Butyl includes sec-butyl, tert-butyl, and iso-butyl. Pentyl includes isopentyl and neopentyl.
  • R is -C 0 -C 4 alkylene-C 3 -Cio carbocyclyl. Further, R is -C0-C4 alkylene-C3-Cio cyclopropyl. Further, R 7 is -Ci alkylene- cyclopropyl or cyclopropyl.
  • R 8 is independently hydrogen, C 3 -C 10 carbocyclyl, 4-13 membered heterocyclyl, fluoro, chloro, -OH,
  • R 8 is methyl
  • R 9 is hydrogen or OH. Specifically, R 9 is hydrogen. Alternatively, R 9 is OH.
  • Each m is independently 0, 1 or 2. Specifically, m is 0.
  • n 1 or 2.
  • p is 0 or an integer between 1 and 4. Specifically, p is 1. Alternatively, p is
  • a first embodiment of the present invention is directed to a compound represented by Structural Formula (I), or a pharmaceutically acceptable salt thereof, wherein:
  • X is selected from hydrogen, bromo, fluoro, chloro, Ci-C 6 alkyl, -0-Ci-C 6 alkyl, C3-C10 carbocyclyl, -O-C3-C10 carbocyclyl, 4-13 membered heterocyclyl, -0-4-13 membered heterocyclyl, -S(0) m -R 2 , -CN, -N(R 2 )(R 3 ), -S(0) m -N(R 2 )(R 3 ), -C(0)-0-R 2 , -C(0)-N(R 2 )(R 3 ), and -NH-C(0)-(Ci-C 6 alkylene)-N(R 2 )(R 3 ), wherein each alkyl, or alkylene in the group represented by X is optionally substituted with one or more fluoro; and
  • Ring E is selected from C 3 -C 10 carbocyclyl and a (4-13 membered) heterocyclyl,
  • W is selected from C(R 6 ), C(R 6 ) 2 , N, and N(R 7 );
  • Q is selected from C(R 6 ), C(R 6 ) 2 , N, N(R 7 ), O, and S;
  • Y is selected from hydrogen, fluoro, bromo, -CN, -[C(R la )(R lb )] admir-N(R 2 )(R 3 ), -N(R 4 )(R 5 ), N0 2 , -NH-C(0)-(Ci-C 4 alkylene)-N(R 4 )(R 5 ), Ci-C 6 alkyl,
  • each R la and R lb is independently selected from hydrogen, C 1 -C4 alkyl, and C3-C10 carbocyclyl;
  • R 2 is selected from hydrogen, alkyl, -C 0 -C 6 alkylene-C 3 -Ci 0 carbocyclyl, and -Co-C 6 alkylene-4-13 membered heterocyclyl;
  • R 3 is selected from hydrogen, Ci-Cg alkyl, -Co-C 6 alkylene-C3-Cio carbocyclyl, -Co-C 6 alkylene-4-13 membered heterocyclyl, -C(0)-Ci-C 6 alkyl, -C 0 -C 6 -alkylene-C(O)N(R 4 )(R 5 ), -C(0)-C C 6 alkylene-N(R 4 )(R 5 ), -C 2 -C 6 alkylene-N(R 4 )(R 5 ), -S(0) m -Ci-C 6 alkyl, -S(O) m -C 3 -Ci 0 carbocyclyl, and
  • each alkyl, carbocyclyl, alkylene or heterocyclyl in the group represented by R 2 or R 3 is optionally and independently substituted with one or more substituents independently selected from fluoro, chloro, -OH, -O-C1-C4 alkyl, C1-C4 alkyl, fluoro-substituted-Ci-C 4 alkyl, -N(R 4 )(R 5 ),
  • R 2 and R 3 taken together with the nitrogen atom to which they are bound form a 4-7 membered monocyclic heterocylic ring, or a 6-13 membered bicyclic, spirocyclic or bridged heterocylic ring wherein:
  • the 4-7 membered monocyclic heterocylic ring, or the 6-13 membered bicyclic, spirocyclic or bridged heterocyclic ring optionally comprises 1 to 4 additional heteroatoms independently selected from N, S and O;
  • each of R 4 and R 5 is independently selected from hydrogen and C1-C4 alkyl
  • each R 6 is independently selected from hydrogen, C3-C10 carbocyclyl, 4-13 membered heterocyclyl, fluoro, chloro, -OH, C1-C4 fluoroalkyl, C1-C4 alkyl, -O-C3- Cio carbocyclyl, -0-4-13 membered heterocyclyl, -C0-C4 alkyl-0-Ci-C4 alkyl,
  • each R 7 is independently selected from hydrogen, -C 0 -C 4 alkylene-C 3 -Ci 0 carbocyclyl, -C0-C4 alkylene-4-13 membered heterocyclyl, -Ci-C 6 fluoroalkyl, -Ci-C 6 alkyl, -O-C3-C10 carbocyclyl, -0-4-13 membered heterocyclyl, -C0-C4 alkylene-0-Ci-C 4 alkyl, -C 0 -C 4 alkylene-0-Ci-C 4 fluoroalkyl, -C(0)-Ci-C 4 alkyl, -C(0)N(R 4 )(R 5 ), -N(R 4 )-C(0)-Ci-C 4 alkyl, and -C 0 -C 4 alkylene-N(R 4 )(R 5 )
  • each m is independently 0, 1 or 2;
  • n 1 or 2;
  • p is 0 or an integer between 1 and 4;
  • Ring E comprises a nitrogen atom, wherein the values for the remaining variables are as defined in the first embodiment or in the values of alternative values described above.
  • W is selected from N(R 7 ) and N, wherein the values for the remaining variables are as defined in the first embodiment or in the values of alternative values described above.
  • Ring E is a 4-7 membered heterocyclyl; Q is C(R 6 ) 2 , and all the other ring atoms in Ring E are carbon, wherein the values for the remaining variables are as defined in the first embodiment or in the values of alternative values described above.
  • Ring E comprises a nitrogen atom, and Ring E is a non-aromatic ring, wherein the values for the remaining variables are as defined in the first embodiment or in the values of alternative values described above.
  • W is selected from N(R 7 ) and N, wherein the values for the remaining variables are as defined in the first embodiment or in the values of alternative values described above.
  • Ring E is a 4-7 membered heterocyclyl; Q is C(R 6 ) 2 , and all the other ring atoms in Ring E are carbon, wherein the values for the remaining variables are as defined in the first embodiment or in the values of alternative values described above.
  • Ring E comprises a ring nitrogen
  • R 7 is selected from hydrogen, -C1-C6 alkyl, -C1-C6 fluoroalkyl, and -C0-C4 alkylene-C3-C10 carbocyclyl, or more specifically, R 7 is hydrogen, -C1-C6 alkyl, - CO-Cl alkylene-C3-C10 carbocyclyl, wherein the values for the remaining variables are as defined in the first embodiment or in the values of alternative values described above.
  • X is selected from hydrogen, chloro, fluoro, -OCH 3 , -OCF 3 , -OCH 2 F, -N(CH 2 ) 3 and CF 3 , or more specifically, X is selected from hydrogen, chloro, fluoro, -OCH 3 , - OCF 3 , and -N(CH 2 ) 3 , wherein the values for the remaining variables are as defined in the first embodiment or in the values of alternative values described above.
  • Y is hydrogen, wherein the values for the remaining variables are as defined in the first embodiment or in the values of alternative values described above.
  • the compound is represented by any one of the compounds depicted in The Figure, or a pharmaceutically acceptable salt thereof.
  • Exemplary compounds represented by Structural Formula (I) are shown below.
  • Diastereomer B S5-4-1-B
  • Diastereomer A S9-12-1 -A
  • Diastereomer A S9-12-3-A Diastereomer A S4-8-6-A Diastereomer B S9-12-3-B Diastereomer B S4-8-6-B
  • diastereomer B S20-9-15-B OH O HO H O O OH O HO H O C diastereomer B S21-16-6-B diastereomer A S21-16-1-A diastereomer A S21-16-6-A diastereomer B S21-16-1-B
  • Alkyl means an optionally substituted saturated aliphatic branched or straight-chain monovalent hydrocarbon radical having the specified number of carbon atoms.
  • (Ci-C 6 ) alkyl means a radical having from 1- 6 carbon atoms in a linear or branched arrangement.
  • (Ci-C 6 )alkyl includes methyl, ethyl, propyl, butyl, pentyl and hexyl.
  • Alkylene means an optionally substituted saturated aliphatic branched or straight-chain divalent hydrocarbon radical having the specified number of carbon atoms.
  • (Ci-C 6 )alkylene means a divalent saturated aliphatic radical having from 1- 6 carbon atoms in a linear arrangement, e.g., -[(CH 2 ) n ]-, where n is an integer from 1 to 6,
  • (Ci-C 6 )alkylene” includes methylene, ethylene, propylene, butylene, pentylene and hexylene.
  • (Ci-C 6 )alkylene means a divalent saturated radical having from 1-6 carbon atoms in a branched arrangement, for example: -[(CH 2 CH 2 CH 2 CH 2 CH(CH 3 )]-, -[(CH 2 CH 2 CH 2 CH 2 C(CH 3 ) 2 ]-, -[(CH 2 C(CH 3 ) 2 CH(CH 3 ))]-, and the like.
  • a s ecific branched C 3 -alkylene is and a specific C 4 -alkylene is
  • Each alkyl or alkylene in Structural Formula I is optionally and
  • Aryl or “aromatic” means an aromatic monocyclic or polycyclic (e.g. bicyclic or tricyclic) carbocyclic ring system.
  • aryl is a 6-12 membered monocylic or bicyclic system.
  • Aryl systems include, but not limited to, phenyl, naphthalenyl, fluorenyl, indenyl, azulenyl, and anthracenyl.
  • Carbocyclyl means a cyclic group with only ring carbon atoms.
  • Carbocyclyl includes 3-12 membered saturated, partially saturated or unsaturated aliphatic cyclic hydrocarbon rings or 6-12 membered aryl rings.
  • a carbocyclyl moiety can be monocyclic, fused bicyclic, bridged bicyclic, spiro bicyclic, or polycyclic.
  • Monocyclic carbocyclyls are saturated or unsaturated aliphatic cyclic hydrocarbon rings or aromatic hydrocarbon rings having the specified number of carbon atoms.
  • Monocyclic carbocyclyls include cycloalkyl, cycloalkenyl, cycloalkynyl and phenyl.
  • a fused bicyclic carbocyclyl has two rings which have two adjacent ring atoms in common.
  • the first ring is a monocyclic carbocyclyl and the second ring is a monocyclic carbocyclyl or a monocyclic heterocyclyl.
  • a bridged bicyclic carbocyclyl has two rings which have three or more adjacent ring atoms in common.
  • the first ring is a monocyclic carbocyclyl and the second ring is a monocyclic carbocyclyl or a monocyclic heterocyclyl.
  • a spiro bicyclic carbocyclyl has two rings which have only one ring atom in common.
  • the first ring is a monocyclic carbocyclyl and the second ring is a monocyclic carbocyclyl or a monocyclic heterocyclyl.
  • Polycyclic carbocyclyls have more than two rings (e.g., three rings resulting in a tricyclic ring system) and adjacent rings have at least one ring atom in common.
  • the first ring is a monocyclic carbocyclyl and the remainder of the ring structures are monocyclic carbocyclyls or monocyclic heterocyclyls.
  • Polycyclic ring systems include fused, bridged and spiro ring systems.
  • a fused poly cyclic ring system has at least two rings that have two adjacent ring atoms in common.
  • a spiro poly cyclic ring system has at least two rings that have only one ring atom in common.
  • a bridged polycyclic ring system has at least two rings that have three or more adjacent ring atoms in common.
  • Cycloalkyl means a saturated aliphatic cyclic hydrocarbon ring.
  • C 3 -C 7 cycloalkyl means a hydrocarbon radical of a (3-7 membered) saturated aliphatic cyclic hydrocarbon ring.
  • a C 3 -C 7 cycloalkyl includes, but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Cycloalkene means an aliphatic cyclic hydrocarbon ring having one or more double bonds in the ring.
  • Cycloalkyne means an aliphatic cyclic hydrocarbon ring having one or more triple bonds in the ring.
  • Hetero refers to the replacement of at least one carbon atom member in a ring system with at least one heteroatom selected from N, S, and O. “Hetero” also refers to the replacement of at least one carbon atom member in an acyclic system.
  • a hetero ring system or a hetero acyclic system may have 1, 2, 3 or 4 carbon atom members replaced by a heteroatom.
  • Heterocyclyl means a cyclic 4-13 membered saturated or unsaturated aliphatic or aromatic ring containing 1, 2, 3, 4 or 5 heteroatoms independently selected from N, O or S. When one heteroatom is S, it can be optionally mono- or di-oxygenated (i.e. -S(O)- or -S(0) 2 -).
  • the heterocyclyl can be monocyclic, fused bicyclic, bridged bicyclic, spiro bicyclic or polycyclic.
  • “Saturated heterocyclyl” means an aliphatic heterocyclyl group without any degree of unsaturation (i.e., no double bond or triple bond). It can be monocyclic, fused bicyclic, bridged bicyclic, spiro bicyclic or polycyclic.
  • monocyclic saturated heterocyclyls include, but are not limited to,
  • azetidine pyrrolidine, piperidine, piperazine, azepane, hexahydropyrimidine, tetrahydrofuran, tetrahydropyran, morpholine, thiomorpholine, thiomorpholine 1,1 -dioxide, tetrahydro-2H-l,2-thiazine, tetrahydro-2H-l,2-thiazine 1,1 -dioxide, isothiazolidine, isothiazolidine 1,1 -dioxide.
  • a fused bicyclic heterocyclyl has two rings which have two adjacent ring atoms in common.
  • the first ring is a monocyclic heterocyclyl and the second ring is a monocyclic carbocycle (such as a cycloalkyl or phenyl) or a monocyclic heterocyclyl.
  • the second ring is a (C 3 -C 6 )cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • the second ring is phenyl.
  • fused bicyclic heterocyclyls include, but are not limited to, octahydrocyclopenta[c]pyrrolyl, indoline, isoindoline,
  • a spiro bicyclic heterocyclyl has two rings which have only one ring atom in common.
  • the first ring is a monocyclic heterocyclyl and the second ring is a monocyclic carbocycle (such as a cycloalkyl or phenyl) or a monocyclic
  • heterocyclyl For example, the second ring is a (C 3 -C6)cycloalkyl. Alternatively, the second ring is phenyl.
  • Example of spiro bicyclic heterocyclyl includes, but are not limited to, azaspiro[4.4]nonane, 7-azaspiro[4.4]nonane, azasprio[4.5]decane, 8-azaspiro[4.5]decane, azaspiro[5.5]undecane, 3-azaspiro[5.5]undecane and 3,9-diazaspiro[5.5]undecane.
  • a bridged bicyclic heterocyclyl has two rings which have three or more adjacent ring atoms in common.
  • the first ring is a monocyclic heterocyclyl and the other ring is a monocyclic carbocycle (such as a cycloalkyl or phenyl) or a monocyclic heterocyclyl.
  • Examples of bridged bicyclic heterocyclyls include, but are not limited to, azabicyclo[3.3.1]nonane, 3-azabicyclo[3.3.1]nonane,
  • Polycyclic heterocyclyls have more than two rings, one of which is a heterocyclyl (e.g., three rings resulting in a tricyclic ring system) and adjacent rings having at least one ring atom in common.
  • Polycyclic ring systems include fused, bridged and spiro ring systems.
  • a fused polycyclic ring system has at least two rings that have two adjacent ring atoms in common.
  • a spiro polycyclic ring system has at least two rings that have only one ring atom in common.
  • a bridged polycyclic ring system has at least two rings that have three or more adjacent ring atoms in common.
  • Heteroaryl or “heteroaromatic ring” means a 5-12 membered monovalent heteroaromatic monocyclic or bicylic ring radical.
  • a herteroaryl contains 1, 2, 3 or 4 heteroatoms independently selected from N, O, and S.
  • Heteroaryls include, but are not limited to furan, oxazole, thiophene, 1,2,3-triazole, 1,2,4-triazine, 1,2,4-triazole, 1,2,5-thiadiazole 1,1-dioxide, 1,2,5-thiadiazole 1-oxide, 1,2,5-thiadiazole, 1,3,4- oxadiazole, 1,3,4-thiadiazole, 1 ,3,5-triazine, imidazole, isothiazole, isoxazole, pyrazole, pyridazine, pyridine, pyridine -N-oxide, pyrazine, pyrimidine, pyrrole, tetrazole, and thiazole.
  • Bicyclic heteroaryl rings include, but are not limited to, bicyclo[4.4.0] and bicyclo[4.3.0] fused ring systems such as indolizine, indole, isoindole, indazole, benzimidazole, benzthiazole, purine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine.
  • each carbocyclyl or heterocyclyl portion of a substituent of ring E is optionally and independently substituted.
  • Halogen used herein refers to fluorine, chlorine, bromine, or iodine.
  • Alkoxy means an alkyl radical attached through an oxygen linking atom.
  • (Ci-C6)-alkoxy includes methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy.
  • Haloalkyl and halocycloalkyl include mono, poly, and perhaloalkyl groups where each halogen is independently selected from fluorine, chlorine, and bromine.
  • Halogen and "halo” are interchangeably used herein and each refers to fluorine, chlorine, bromine, or iodine.
  • Fruoro means -F.
  • fluoro-substituted-(Ci-C )alkyl means a (Ci-C )alkyl substituted with one or more -F groups.
  • fluoro-substituted-(Ci-C 4 )alkyl include, but are not limited to, -CF 3 , -CH 2 CF 3 , -CH 2 CF 2 H, -CH 2 CH 2 F and -CH 2 CH 2 CF 3 .
  • “Naturally occurring amino acid side chain moiety” refers to any amino acid side chain moiety present in a natural amino acid.
  • compositions comprising one or more pharmaceutically acceptable carrier and/or diluent and a compound disclosed herein or a pharmaceutically acceptable salt thereof.
  • pharmaceutically acceptable carrier and “pharmaceutically acceptable diluent” means non-therapeutic components that are of sufficient purity and quality for use in the formulation of a composition of the invention that, when appropriately administered to an animal or human, typically do not produce an adverse reaction, and that are used as a vehicle for a drug substance (i.e. a compound of the present invention).
  • compositions of the present invention are also included.
  • an acid salt of a compound of the present invention containing an amine or other basic group can be obtained by reacting the compound with a suitable organic or inorganic acid, resulting in pharmaceutically acceptable anionic salt forms.
  • anionic salts include the acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,
  • Salts of the compounds of the present invention containing a carboxylic acid or other acidic functional group can be prepared by reacting with a suitable base.
  • a pharmaceutically acceptable salt may be made with a base which affords a pharmaceutically acceptable cation, which includes alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and
  • magnesium aluminum salts and ammonium salts, as well as salts made from physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine,
  • ⁇ , ⁇ '-dibenzylethylenediamine 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine, dehydroabietylamine, ⁇ , ⁇ '-bisdehydroabietylamine, glucamine, N-methylglucamine, collidine, quinine, quinoline, and basic amino acids such as lysine and arginine.
  • the invention also includes various isomers and mixtures thereof. Certain of the compounds of the present invention may exist in various stereoisomeric forms. Stereoisomers are compounds which differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. "Enantiomer” means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms. "R” and “S” represent the configuration of substituents around one or more chiral carbon atoms. When a chiral center is not defined as R or S, either a pure enantiomer or a mixture of both configurations is present.
  • Racemate or “racemic mixture” means a compound of equimolar quantities of two enantiomers, wherein such mixtures exhibit no optical activity; i.e., they do not rotate the plane of polarized light.
  • the compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture.
  • Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods.
  • the stereochemistry of a disclosed compound is named or depicted by structure
  • the named or depicted stereoisomer is at least 60%, 70%>, 80%>, 90%>, 99% or 99.9% by weight pure relative to the other stereoisomers.
  • the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight optically pure. Percent optical purity by weight is the ratio of the weight of the enantiomer that is present divided by the combined weight of the enantiomer that is present and the weight of its optical isomer.
  • the present invention also provides a method for treating or preventing an infection or colonization in a subject comprising administering to the subject an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a method of treating or preventing a subject with a tetracycline-responsive disease or disorder comprising administering to the subject an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.
  • Tetracycline-responsive disease or disorder refers to a disease or disorder that can be treated, prevented, or otherwise ameliorated by the administration of a tetracycline compound of the present invention. Tetracycline-responsive disease or disorder includes infections, cancer, inflammatory disorders, autoimmune disease, arteriosclerosis, corneal ulceration, emphysema, arthritis, osteoporosis,
  • osteoarthritis multiple sclerosis, osteosarcoma, osteomyelitis, bronchiectasis, chronic pulmonary obstructive disease, skin and eye diseases, periodontitis, osteoporosis, rheumatoid arthritis, ulcerative colitis, prostatitis, tumor growth and invasion, metastasis, diabetes, diabetic proteinuria, panbronchio litis, aortic or vascular aneurysms, skin tissue wounds, dry eye, bone, cartilage degradation, malaria, senescence, diabetes, vascular stroke, neurodegenerative disorders, cardiac disease, juvenile diabetes, acute and chronic bronchitis, sinusitis, and respiratory infections, including the common cold, Wegener's granulomatosis; neutrophilic dermatoses and other inflammatory diseases such as dermatitis herpetiformis, leukocytoclastic vasculitis, bullous lupus erythematosus, pustular psoriasis, erythema elevatum
  • a method to treat any disease or disease state that could benefit from modulating the expression and/or function of C-reactive protein, signaling pathways (e.g., FAK signaling pathway), and/or augment the expression of COX-2 and PGE 2 production is covered.
  • a method to treat any disease or disease state that could benefit from inhibition of neovascularization is covered.
  • Compounds of the invention can be used to prevent or treat important mammalian and veterinary diseases such as diarrhea, urinary tract infections, infections of skin and skin structure including wounds, cellulitis, and abscesses, ear, nose and throat infections, mastitis and the like.
  • important mammalian and veterinary diseases such as diarrhea, urinary tract infections, infections of skin and skin structure including wounds, cellulitis, and abscesses, ear, nose and throat infections, mastitis and the like.
  • methods for treating neoplasms using tetracycline compounds of the invention are also included (van der Bozert et al, Cancer Res., 48: 6686-6690 (1988)).
  • Infections that can be treated using compounds of the invention or a pharmaceutically acceptable salt thereof include, but are not limited to, skin infections, GI infections, urinary tract infections, genito-urinary infections, respiratory tract infections, sinuses infections, middle ear infections, systemic infections, intra-abdominal infections, pyelonephritis, pneumonia, bacterial vaginosis, streptococcal sore throat, chronic bacterial prostatitis, gynecological and pelvic infections, sexually transmitted bacterial diseases, ocular and otic infections, cholera, influenza, bronchitis, acne, psoriasis, rosacea, impetigo, malaria, sexually transmitted disease including syphilis and gonorrhea, Legionnaires' disease, Lyme disease, Rocky Mountain spotted fever, Q fever, typhus, bubonic plague, gas gangrene, hospital acquired infections, leptospirosis, whooping cough, anthrax and infections caused by the agents responsible
  • Infections can be bacterial, fungal, parasitic and viral infections (including those which are resistant to other tetracycline compounds). Specifically, the infections are pyelonephritis or urinary tract infections. In another embodiment, the compound of the invention can be used for urinary tract infections (UTI), chronic urinary tract infections (cUTI) or
  • the compounds of the invention can be used to treat an infection selected from an urinary tract infection, a respiratory tract infection, an intra-abdominal infection, an acute or chronic skin and skin structure infection and pneumonia.
  • the urinary tract infection, respiratory tract infection, intra-abdominal infection, acute or chronic skin and skin structure infection or preumonia is hospital acquired.
  • the urinary tract infection, respiratory tract infection, intra-abodominal infection, acute or chronic skin and skin structure infection or pneumonia, which may be hospital acquired is caused by a gram negative organism.
  • the gram-negative organism is P. aeruginosa and K. pneumonia.
  • the gram-negative organism is Enterobacteriaceae.
  • the infection is a urinary tract infection (e.g., a hospital acquired urinary tract infection or a complicated urinary tract infection which can also be hospital acquired).
  • the infection is an intra-abdominal infection, such as a complicated intra-abdominal infection which can also be hospital acquired.
  • the infection is pneumonia (e.g., healthcare associated pneumonia, ventilator- acquired pneumonia or moderate to severe community-associated pneumonia).
  • the infection is an acute or chronic bacterial skin and skin structure infection (e.g., a mono- or poly microbial skin infection).
  • the chronic bacterial skin and skin structure infection is selected from a diabetic foot infection, a skin infection that requires treatment more than 10-14 days or a skin infection that requires intermittent antimicrobial therapy.
  • the compounds of the invention can be used to treat an infection selected from an urinary tract infection, a respiratory tract infection, an intra abdominal infection, an acute or chronic skin and skin structure infection and pneumonia that is caused by a gram negative organism (e.g., P. aeruginosa or K. pneumonia) and at least one other organism selected from Acinetobacter spp., Burkholderia spp., ESpL- and carbapenum-resistant Enterobacteriaceae, MRSA and anaerobes.
  • the infection can be caused by a bacterium (e.g. an anaerobic or aerobic bacterium).
  • the infection is caused by a Gram-positive bacterium.
  • the infection is caused by a Gram-positive bacterium selected from class Bacilli, including, but not limited to, Staphylococcus spp., Streptococcus spp., Enterococcus spp., Bacillus spp., Listeria spp.; phylum Actinobacteria, including, but not limited to, Propionibacterium spp., Corynebacterium spp., Nocardia spp., Actinobacteria spp., and class Clostridia, including, but not limited to, Clostridium spp.
  • the infection is caused by a Gram-negative bacterium.
  • the infection is caused by a phylum Proteobacteria (e.g., Betaproteobacteria and Gammaproteobacteria), including Escherichia coli, Salmonella, Shigella, other Enter obacteriaceae, Pseudomonas, Moraxella, Helicobacter, Stenotrophomonas, Bdellovibrio, acetic acid bacteria, Legionella or alpha-proteobacteria such as Wolbachia.
  • a phylum Proteobacteria e.g., Betaproteobacteria and Gammaproteobacteria
  • the infection is caused by a Gram-negative bacterium selected from cyanobacteria, spirochaetes, green sulfur or green non-sulfur bacteria.
  • the infection is caused by a Gram-negative bacteria selected from Enter ob actericeae (e.g., E.
  • Vibrionaceae (Vibrio cholerae), Pasteur ellaceae (e.g., Haemophilus influenzae), Pseudomonadaceae (e.g., Pseudomonas aeruginosa), Neisseriaceae (e.g.
  • the infection is caused by Gram-negative bacterium selected from the group consisting of Enter ob actericeae (e.g., E. coli, Klebsiella pneumoniae), Pseudomonas, and Acinetobacter spp.
  • the infection is caused by an organism selected from the group consisting of K. pneumoniae, Salmonella, E. hirae, A. baumanii, M. catarrhalis, H. influenzae, P. aeruginosa, E. faecium, E. coli, S. aureus, and E.faecalis.
  • the infection is caused by one or more multi-drug resistant (MDR) Gram-negative bacterium.
  • MDR multi-drug resistant
  • the infection is caused by ESBL or carbapenum- resistant bacteria. In one embodiment, the infection is caused by an organism that grows intracellularly as part of its infection process.
  • the infection is caused by an organism selected from the group consisting of order Rickettsiales; phylum Chlamydiae; order
  • Mycobacterium tuberculosis Mycobacterium tuberculosis
  • phylum Spriochaetales e.g. Borrelia spp. and Treponema spp.
  • the infection is caused by a Category A Biodefense organism as described at http://www.bt.cdc.gov/agent/agentlist-category.asp, the entire teachings of which are incorporated herein by reference.
  • Category A organisms include, but are not limited to, Bacillus anthracis (anthrax), Yersinia pestis (plague), Clostridium botulinum (botulism) or Francisella tularensis (tularemia).
  • the infection is a Bacillus anthracis infection.
  • Bacillus anthracis infection includes any state, diseases, or disorders caused or which result from exposure or alleged exposure to Bacillus anthracis or another member of the Bacillus cereus group of bacteria.
  • Additional infections that can be treated using compounds of the invention or a pharmaceutically acceptable salt thereof include, but are not limited to, anthrax, botulism, bubonic plague, and tularemia.
  • the infection is caused by a Category B Biodefense organism as described at http://www.bt.cdc.gov/agent/agentlist-category.asp, the entire teachings of which are incorporated herein by reference.
  • Category B organisms include, but are not limited to, Brucella spp, Clostridium perfringens, Salmonella spp., Escherichia coli 0157:H7, Shigella spp., Burkholderia mallei, Burkholderia pseudomallei, Chlamydia psittaci, Coxiella burnetii,
  • Staphylococcal enterotoxin B Rickettsia prowazekii, Vibrio cholerae
  • Additional infections that can be treated using compounds of the invention or a pharmaceutically acceptable salt thereof include, but are not limited to,
  • the infection can be caused by one or more than one organism described above.
  • infections include, but are not limited to, intra-abdominal infections (often a mixture of a gram-negative species like E. coli and an anaerobe like B. fragilis), diabetic foot (various combinations of Streptococcus, Serratia, Staphylococcus and Enterococcus spp., anaerobes (S.E. Dowd, et al, PloS one 2008;3:e3326, the entire teachings of which are incorporated herein by reference) and respiratory disease (especially in patients that have chronic infections like cystic fibrosis - e.g., S. aureus plus P.
  • aeruginosa or H. influenzae atypical pathogens
  • wounds and abscesses variant gram-negative and gram- positive bacteria, notably MSSA/MRSA, coagulase-negative staphylococci, enterococci, Acinetobactex, P. aeruginosa, E. coli, B. fragilis
  • bloodstream infections (13% were polymicrobial (H. Wisplinghoff, et al., Clin. Infect. Dis.
  • the infection is caused by an organism resistant to one or more antibiotics.
  • the infection is caused by an organism resistant to tetracycline or any member of first and second generation of tetracycline antibiotics (e.g., doxycycline or minocycline).
  • tetracycline antibiotics e.g., doxycycline or minocycline.
  • the infection is caused by an organism resistant to methicillin or any antibiotic in the ⁇ -lactam class. More specifically, the infection is caused by an organism resistant to methicillin.
  • the infection is caused by an organism resistant to vancomycin.
  • the infection is caused by an organism resistant to a quinolone or fluoroquinolone.
  • the infection is caused by an organism resistant to tigecycline or any other tetracycline derivative. In a particular embodiment, the infection is caused by an organism resistant to tigecycline.
  • the infection is caused by an organism resistant to a ⁇ -lactam or cephalosporin antibiotic or an organism resistant to penems or carbapenems.
  • the infection is caused by an organism resistant to an antimicrobial peptide or a biosimilar therapeutic treatment.
  • Antimicrobial peptides also called host defense peptides
  • antimicrobial peptides are an evolutionarily conserved component of the innate immune response and are found among all classes of life.
  • antimicrobial peptide refers to any naturally occurring molecule or any combination thereof.
  • the infection is caused by an organism resistant to macrolides, lincosamides, streptogramin antibiotics, oxazolidinones, and
  • the infection is caused by an organism resistant to PTK0796 (7-dimethylamino, 9-(2,2-dimethyl-propyl)-aminomethylcycline).
  • the infection is caused by a multidrug-resistant pathogen (having intermediate or full resistance to any two or more antibiotics).
  • the infection is caused by ESBL- and
  • the infection is caused by E. coli EC200 or K pneumoniae KP453.
  • the compound of the invention can be used in IV/oral monotherapy against multi-drug resistant gram-negative bacteria.
  • the tetracycline responsive disease or disorder is not a bacterial infection.
  • the tetracycline compounds of the invention are essentially non-antibacterial.
  • non-antibacterial compounds of the invention may have MIC values greater than about 4 ⁇ g/ml (as measured by assays known in the art and/or the assay given in Example 32.
  • the tetracycline compounds of the invention have both antibacterial and non-antibacterial effects.
  • Tetracycline responsive disease or disorder also includes diseases or disorders associated with inflammatory process associated states (IP AS).
  • inflammatory process associated state includes states in which inflammation or inflammatory factors (e.g., matrix metalloproteinases (MMPs), nitric oxide (NO), TNF, interleukins, plasma proteins, cellular defense systems, cytokines, lipid metabolites, proteases, toxic radicals, adhesion molecules, etc.) are involved or are present in an area in aberrant amounts, e.g., in amounts which may be advantageous to alter, e.g., to benefit the subject.
  • MMPs matrix metalloproteinases
  • NO nitric oxide
  • TNF interleukins
  • plasma proteins e.g., plasma proteins
  • cellular defense systems e.g., cytokines, lipid metabolites, proteases, toxic radicals, adhesion molecules, etc.
  • the inflammatory process is the response of living tissue to damage.
  • the cause of inflammation may be due to physical damage,
  • Acute inflammation is short- lasting, lasting only a few days. If it is longer lasting however, then it may be referred to as chronic inflammation.
  • IPASs include inflammatory disorders. Inflammatory disorders are generally characterized by heat, redness, swelling, pain and loss of function. Examples of causes of inflammatory disorders include, but are not limited to, microbial infections (e.g., bacterial and fungal infections), physical agents (e.g., burns, radiation, and trauma), chemical agents (e.g., toxins and caustic substances), tissue necrosis and various types of immunologic reactions.
  • microbial infections e.g., bacterial and fungal infections
  • physical agents e.g., burns, radiation, and trauma
  • chemical agents e.g., toxins and caustic substances
  • inflammatory disorders can be treated using the compounds of the invention or a pharmaceutically acceptable salt thereof include, but are not limited to, osteoarthritis, rheumatoid arthritis, acute and chronic infections (bacterial and fungal, including diphtheria and pertussis); acute and chronic bronchitis, sinusitis, and upper respiratory infections, including the common cold; acute and chronic gastroenteritis and colitis; inflammatory bowel disorder; acute and chronic cystitis and urethritis; vasculitis; sepsis; nephritis; pancreatitis; hepatitis; lupus; inflammatory skin disorders including, for example, eczema, dermatitis, psoriasis, pyoderma gangrenosum, acne rosacea, and acute and chronic dermatitis; acute and chronic conjunctivitis; acute and chronic serositis (pericarditis, peritonitis, synovitis, pleuritis and tendinitis);
  • IPASs also include matrix metalloproteinase associated states (MMPAS).
  • MMPAS include states characterized by aberrant amounts of MMPs or MMP activity.
  • MMP's matrix metalloproteinase associated states
  • MMP's matrix metalloproteinase associated states
  • arteriosclerosis corneal ulceration
  • emphysema emphysema
  • osteoarthritis emphysema
  • multiple sclerosis Liedtke et al, Ann. Neurol. 1998, 44: 35-46; Chandler et al, J. Neuroimmunol.
  • MMPAS include those described in U. S. Pat. Nos. 5,459,135; 5,321,017; 5,308,839; 5,258,371; 4,935,412; 4,704,383, 4,666,897, and RE 34,656, incorporated herein by reference in their entirety.
  • the IPAS includes disorders described in U. S. Patents Nos. 5,929,055; and 5,532,227, incorporated herein by reference in their entirety.
  • Tetracycline responsive disease or disorder also includes diseases or disorders associated with NO associated states.
  • NO associated states includes states which involve or are associated with nitric oxide (NO) or inducible nitric oxide synthase (iNOS).
  • NO associated state includes states which are characterized by aberrant amounts of NO and/or iNOS.
  • the NO associated state can be treated by administering tetracycline compounds of the invention.
  • diseases or disorders associated with NO associated states can be treated using the compounds of the present invention or a pharmaceutically acceptable salt thereof include, but are not limited to, malaria, senescence, diabetes, vascular stroke, neurodegenerative disorders (Alzheimer's disease and Huntington's disease), cardiac disease (reperfusion-associated injury following infarction), juvenile diabetes, inflammatory disorders, osteoarthritis, rheumatoid arthritis, acute, recurrent and chronic infections (bacterial, viral and fungal); acute and chronic bronchitis, sinusitis, and respiratory infections, including the common cold; acute and chronic gastroenteritis and colitis; acute and chronic cystitis and urethritis; acute and chronic dermatitis; acute and chronic conjunctivitis; acute and chronic serositis (pericarditis, peritonitis, synovitis, pleuritis and tendonitis); uremic pericarditis; acute and chronic cholecystis; cystic fibrosis, acute and chronic vaginitis
  • the tetracycline responsive disease or disorder is cancer.
  • cancers that can be treated using the compounds of the invention or a pharmaceutically acceptable salt thereof include all solid tumors, i.e., carcinomas e.g., adenocarcinomas, and sarcomas.
  • carcinomas e.g., adenocarcinomas
  • sarcomas are carcinomas derived from glandular tissue or in which the tumor cells form recognizable glandular structures.
  • Sarcomas broadly include tumors whose cells are embedded in a fibrillar or homogeneous substance like embryonic connective tissue.
  • carcinomas which may be treated using the methods of the invention include, but are not limited to, carcinomas of the prostate, breast, ovary, testis, lung, colon, and breast.
  • the methods of the invention are not limited to the treatment of these tumor types, but extend to any solid tumor derived from any organ system.
  • treatable cancers include, but are not limited to, colon cancer, bladder cancer, breast cancer, melanoma, ovarian carcinoma, prostate carcinoma, lung cancer, and a variety of other cancers as well.
  • the methods of the invention also cause the inhibition of cancer growth in adenocarcinomas, such as, for example, those of the prostate, breast, kidney, ovary, testes, and colon.
  • the cancers treated by methods of the invention include those described in U. S. Patent Nos. 6,100,248; 5,843,925; 5,837,696; or 5,668,122, incorporated herein by reference in their entirety.
  • the tetracycline compounds may be useful for preventing or reducing the likelihood of cancer recurrence, for example, to treat residual cancer following surgical resection or radiation therapy.
  • the tetracycline compounds useful according to the invention are especially advantageous as they are
  • the compounds of the invention are administered in combination with standard cancer therapy, such as, but not limited to, chemotherapy.
  • Examples of tetracycline responsive states can be treated using the compounds of the invention or a pharmaceutically acceptable salt thereof also include neurological disorders which include both neuropsychiatric and
  • neurodegenerative disorders include Alzheimer's disease, dementias related to Alzheimer's disease (such as Pick's disease), Parkinson's and other Lewy diffuse body diseases, senile dementia, Huntington's disease, Gilles de la Tourette's syndrome, multiple sclerosis, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy, epilepsy, and Creutzfeldt- Jakob disease; autonomic function disorders such as hypertension and sleep disorders, and neuropsychiatric disorders, such as depression, schizophrenia, schizoaffective disorder, Korsakoff s psychosis, mania, anxiety disorders, or phobic disorders; learning or memory disorders, e.
  • Alzheimer's disease dementias related to Alzheimer's disease (such as Pick's disease), Parkinson's and other Lewy diffuse body diseases, senile dementia, Huntington's disease, Gilles de la Tourette's syndrome, multiple sclerosis, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy, epi
  • bipolar affective disorder e. g., severe bipolar affective (mood) disorder (BP-1), bipolar affective neurological disorders, e. g. , migraine and obesity.
  • Further neurological disorders include, for example, those listed in the American Psychiatric Association's Diagnostic and Statistical manual of Mental Disorders (DSM), the most current version of which is incorporated herein by reference in its entirety.
  • DSM Diagnostic and Statistical manual of Mental Disorders
  • the tetracycline responsive disease or disorder is diabetes.
  • Diabetes that can be treated using the compounds of the invention or a pharmaceutically acceptable salt thereof include, but are not limited to, juvenile diabetes, diabetes mellitus, diabetes type I, or diabetes type II.
  • protein glycosylation is not affected by the administration of the tetracycline compounds of the invention.
  • the tetracycline compound of the invention is administered in combination with standard diabetic therapies, such as, but not limited to insulin therapy.
  • the tetracycline responsive disease or disorder is a bone mass disorder.
  • Bone mass disorders that can be treated using the compounds of the invention or a pharmaceutically acceptable salt thereof include disorders where a subjects bones are disorders and states where the formation, repair or remodeling of bone is advantageous.
  • bone mass disorders include osteoporosis (e. g. , a decrease in bone strength and density), bone fractures, bone formation associated with surgical procedures (e. g., facial reconstruction), osteogenesis imperfecta (brittle bone disease), hypophosphatasia, Paget's disease, fibrous dysplasia, osteopetrosis, myeloma bone disease, and the depletion of calcium in bone, such as that which is related to primary hyperparathyroidism.
  • Bone mass disorders include all states in which the formation, repair or remodeling of bone is advantageous to the subject as well as all other disorders associated with the bones or skeletal system of a subject which can be treated with the tetracycline compounds of the invention.
  • the bone mass disorders include those described in U. S. Patents Nos. 5,459,135; 5,231,017; 5,998,390; 5,770,588; RE 34,656; 5,308,839; 4,925,833; 3,304,227; and 4,666,897, each of which is hereby incorporated herein by reference in its entirety.
  • the tetracycline responsive disease or disorder is acute lung injury.
  • Acute lung injuries that can be treated using the compounds of the invention or a pharmaceutically acceptable salt thereof include adult respiratory distress syndrome (ARDS), post-pump syndrome (PPS), and trauma.
  • Trauma includes any injury to living tissue caused by an extrinsic agent or event. Examples of trauma include, but are not limited to, crush injuries, contact with a hard surface, or cutting or other damage to the lungs.
  • the tetracycline responsive disease or disorders of the invention also include chronic lung disorders.
  • chronic lung disorders that can be treated using the compounds of the invention or a pharmaceutically acceptable salt thereof include, but are not limited, to asthma, cystic fibrosis, chronic obstructive pulmonary disease (COPD), and emphysema.
  • COPD chronic obstructive pulmonary disease
  • the acute and/or chronic lung disorders that can be treated using the compounds of the invention or a pharmaceutically acceptable salt thereof include those described in U. S. Patents No. 5,977,091; 6,043,231; 5,523,297; and 5,773,430, each of which is hereby
  • the tetracycline responsive disease or disorder is ischemia, stroke, or ischemic stroke.
  • the tetracycline compounds of the invention or a pharmaceutically acceptable salt thereof can be used to treat such disorders as described above and in U. S. Patents No. 6,231,894; 5,773,430; 5,919,775 and 5,789,395, incorporated herein by reference.
  • the tetracycline compounds of the invention or a pharmaceutically acceptable salt thereof can be used to treat pain, for example, inflammatory, nociceptive or neuropathic pain.
  • the pain can be either acute or chronic.
  • the tetracycline responsive disease or disorder is a skin wound.
  • the invention also provides a method for improving the healing response of the epithelialized tissue (e.g., skin, mucosae) to acute traumatic injury (e.g., cut, burn, scrape, etc.).
  • the method includes using a tetracycline compound of the invention or a pharmaceutically acceptable salt thereof to improve the capacity of the epithelialized tissue to heal acute wounds.
  • the method may increase the rate of collagen accumulation of the healing tissue.
  • the method may also decrease the proteolytic activity in the epithelialized tissue by decreasing the collagenolytic and/or gellatinolytic activity of MMPs.
  • the tetracycline compound of the invention or a pharmaceutically acceptable salt thereof is administered to the surface of the skin (e. g., topically).
  • the tetracycline compound of the invention or a pharmaceutically acceptable salt thereof is used to treat a skin wound, and other such disorders as described in, for example, U. S. Patent Nos. 5,827,840; 4,704,383; 4,935,412; 5,258,371; 5,308,839, 5,459,135; 5,532,227; and 6,015,804; each of which is incorporated herein by reference in its entirety.
  • the tetracycline responsive disease or disorder is an aortic or vascular aneurysm in vascular tissue of a subject (e.g., a subject having or at risk of having an aortic or vascular aneurysm, etc.).
  • the tetracycline compound or a pharmaceutically acceptable salt thereof may be effective to reduce the size of the vascular aneurysm or it may be administered to the subject prior to the onset of the vascular aneurysm such that the aneurysm is prevented.
  • the vascular tissue is an artery, e.g., the aorta, e.g., the abdominal aorta.
  • the tetracycline compounds of the invention are used to treat disorders described in U. S. Patent Nos. 6,043,225 and 5,834,449, incorporated herein by reference in their entirety.
  • the compounds of the invention or a pharmaceutically acceptable salt thereof can be used alone or in combination with one or more therapeutic agent in the methods of the invention disclosed herein.
  • combination with includes co-administration of the tetracycline compound and with the other therapeutic agent or treatment as either a single combination dosage form or as multiple, separate dosage forms, administration of the tetracycline compound first, followed by the other therapeutic agent or treatment and administration of the other therapeutic agent or treatment first, followed by the tetracycline compound.
  • compounds of the invention or a pharmaceutically acceptable salt thereof can be used as a monotherapy (either IV or Oral) for infections caused by one or more multi-drug resistant (MDR) Gram-negative bacterium.
  • MDR multi-drug resistant
  • compounds of the invention or a pharmaceutically acceptable salt thereof can be used as a monotherapy (either IV or Oral) for treatment of urinary tract infections (UTI) , chronic urinary tract infections (cUTI) or pyelonephritis.
  • the other therapeutic agent may be any agent that is known in the art to treat, prevent, or reduce the symptoms of a tetracycline-responsive disease or disorder.
  • additional therapeutic agent(s) is based upon the particular
  • the other therapeutic agent may be any agent of benefit to the patient when administered in combination with the administration of a tetracycline compound.
  • the compounds of the invention or a pharmaceutically acceptable salt thereof can be used alone or in combination with one or more antibiotics and/or immunomodulators (e.g. Deoxycholic acid, Macrokine, Abatacept, Belatacept, Infliximab, Adalimumab, Certolizumab pegol, Afelimomab, Golimumab, and FKBP/Cyclophilin/Calcineurin: Tacrolimus, Ciclosporin, Pimecrolimus).
  • antibiotics and/or immunomodulators e.g. Deoxycholic acid, Macrokine, Abatacept, Belatacept, Infliximab, Adalimumab, Certolizumab pegol, Afelimomab, Golimumab, and FKBP/Cyclophilin/Calcineurin: Tacrolimus, Ciclosporin, Pimecrolimus).
  • the term "subject” means a mammal in need of treatment or prevention, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like).
  • the subject is a human in need of the specified treatment.
  • treating refers to obtaining desired pharmacological and/or physiological effect.
  • the effect can include achieving, partially or substantially, one or more of the following results: partially or totally reducing the extent of the disease, disorder or syndrome; ameliorating or improving a clinical symptom or indicator associated with the disorder; delaying, inhibiting or decreasing the likelihood of the progression of the disease, disorder or syndrome.
  • preventing or “prevention” refers to reducing the likelihood of the onset or development of disease, disorder or syndrome.
  • Effective amount means that amount of active compound agent that elicits the desired biological response in a subject.
  • the effective amount of a compound of the invention is from about 0.01 mg/kg/day to about 1000 mg/kg/day, from about 0.1 mg/kg/day to about 100 mg/kg/day, or from about 0.5 mg/kg/day to about 50 mg/kg/day.
  • the invention includes a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and any one of the compounds of the invention.
  • the invention further includes the process for making the composition comprising mixing one or more of the present compounds and an optional pharmaceutically acceptable carrier; and includes those compositions resulting from such a process, which process includes conventional pharmaceutical techniques.
  • compositions of the invention include ocular, oral, nasal, transdermal, topical with or without occlusion, intravenous (both bolus and infusion), inhalable, and injection (intraperitoneally, subcutaneous ly, intramuscularly, intratumorally, or parenterally) formulations.
  • the composition may be in a dosage unit such as a tablet, pill, capsule, powder, granule, liposome, ion exchange resin, sterile ocular solution, or ocular delivery device (such as a contact lens and the like facilitating immediate release, timed release, or sustained release), parenteral solution or suspension, metered aerosol or liquid spray, drop, ampoule, auto-injector device, or suppository; for administration ocularly, orally, intranasally, sublingually, parenterally, or rectally, or by inhalation or insufflation.
  • a dosage unit such as a tablet, pill, capsule, powder, granule, liposome, ion exchange resin, sterile ocular solution, or ocular delivery device (such as a contact lens and the like facilitating immediate release, timed release, or sustained release), parenteral solution or suspension, metered aerosol or liquid spray, drop, ampoule, auto-injector device, or suppository; for administration
  • compositions of the invention suitable for oral administration include solid forms such as pills, tablets, caplets, capsules (each including immediate release, timed release, and sustained release formulations), granules and powders; and, liquid forms such as solutions, syrups, elixirs, emulsions, and suspensions.
  • forms useful for ocular administration include sterile solutions or ocular delivery devices.
  • forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.
  • compositions of the invention may be administered in a form suitable for once-weekly or once-monthly administration.
  • an insoluble salt of the active compound may be adapted to provide a depot preparation for intramuscular injection (e.g., a decanoate salt) or to provide a solution for ophthalmic
  • the dosage form containing the composition of the invention contains an effective amount of the active ingredient necessary to provide a therapeutic effect.
  • the composition may contain from about 5,000 mg to about 0.5 mg (preferably, from about 1,000 mg to about 0.5 mg) of a compound of the invention or salt form thereof and may be constituted into any form suitable for the selected mode of administration.
  • the composition may be administered about 1 to about 5 times per day. Daily administration or post-periodic dosing may be employed.
  • the composition is preferably in the form of a tablet or capsule containing, e.g., 500 to 0.5 milligrams of the active compound. Dosages will vary depending on factors associated with the particular patient being treated (e.g., age, weight, diet, and time of administration), the severity of the condition being treated, the compound being employed, the mode of administration, and the strength of the preparation.
  • the oral composition is preferably formulated as a homogeneous
  • compositions wherein the active ingredient is dispersed evenly throughout the mixture, which may be readily subdivided into dosage units containing equal amounts of a compound of the invention.
  • the compositions are prepared by mixing a compound of the invention (or pharmaceutically acceptable salt thereof) with one or more optionally present pharmaceutical carriers (such as a starch, sugar, diluent, granulating agent, lubricant, glidant, binding agent, and disintegrating agent), one or more optionally present inert pharmaceutical excipients (such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and syrup), one or more optionally present conventional tableting ingredients (such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, and any of a variety of gums), and an optional diluent (such as water).
  • pharmaceutical carriers such as a starch, sugar, diluent, granulating
  • Binder agents include starch, gelatin, natural sugars (e.g., glucose and beta-lactose), corn sweeteners and natural and synthetic gums (e.g., acacia and tragacanth).
  • Disintegrating agents include starch, methyl cellulose, agar, and bentonite.
  • Tablets and capsules represent an advantageous oral dosage unit form.
  • Tablets may be sugarcoated or filmcoated using standard techniques. Tablets may also be coated or otherwise compounded to provide a prolonged, control-release therapeutic effect.
  • the dosage form may comprise an inner dosage and an outer dosage component, wherein the outer component is in the form of an envelope over the inner component.
  • the two components may further be separated by a layer which resists disintegration in the stomach (such as an enteric layer) and permits the inner component to pass intact into the duodenum or a layer which delays or sustains release.
  • enteric and non-enteric layer or coating materials such as polymeric acids, shellacs, acetyl alcohol, and cellulose acetate or combinations thereof may be used.
  • Compounds of the invention may also be administered via a slow release composition; wherein the composition includes a compound of the invention and a biodegradable slow release carrier (e.g., a polymeric carrier) or a pharmaceutically acceptable non-biodegradable slow release carrier (e.g., an ion exchange carrier).
  • a biodegradable slow release carrier e.g., a polymeric carrier
  • a pharmaceutically acceptable non-biodegradable slow release carrier e.g., an ion exchange carrier
  • Biodegradable and non-biodegradable slow release carriers are well known in the art.
  • Biodegradable carriers are used to form particles or matrices which retain an active agent(s) and which slowly degrade/dissolve in a suitable environment (e.g., aqueous, acidic, basic and the like) to release the agent.
  • a suitable environment e.g., aqueous, acidic, basic and the like
  • the particles are preferably nanoparticles or nanoemulsions (e.g., in the range of about 1 to 500 nm in diameter, preferably about 50-200 nm in diameter, and most preferably about 100 nm in diameter).
  • a slow release carrier and a compound of the invention are first dissolved or dispersed in an organic solvent.
  • the resulting mixture is added into an aqueous solution containing an optional surface-active agent(s) to produce an emulsion.
  • the organic solvent is then evaporated from the emulsion to provide a colloidal suspension of particles containing the slow release carrier and the compound of the invention.
  • the compound disclosed herein may be incorporated for administration orally or by injection in a liquid form such as aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil and the like, or in elixirs or similar pharmaceutical vehicles.
  • aqueous solutions suitably flavored syrups, aqueous or oil suspensions, flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil and the like, or in elixirs or similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose,
  • liquid forms in suitably flavored suspending or dispersing agents may also include synthetic and natural gums.
  • suspending or dispersing agents may also include synthetic and natural gums.
  • sterile suspensions and solutions are desired.
  • Isotonic preparations, which generally contain suitable preservatives, are employed when intravenous administration is desired.
  • a parenteral formulation may consist of the active ingredient dissolved in or mixed with an appropriate inert liquid carrier.
  • Acceptable liquid carriers usually comprise aqueous solvents and other optional ingredients for aiding solubility or preservation.
  • aqueous solvents include sterile water, Ringer's solution, or an isotonic aqueous saline solution.
  • Other optional ingredients include vegetable oils (such as peanut oil, cottonseed oil, and sesame oil), and organic solvents (such as solketal, glycerol, and formyl).
  • a sterile, non-volatile oil may be employed as a solvent or suspending agent.
  • the parenteral formulation is prepared by dissolving or suspending the active ingredient in the liquid carrier whereby the final dosage unit contains from 0.005 to 10% by weight of the active ingredient.
  • Other additives include preservatives, isotonizers, solubilizers, stabilizers, and pain-soothing agents. Injectable
  • suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • Compounds of the invention may be administered intranasally using a suitable intranasal vehicle.
  • the compounds of this invention may be any organic compound having the same or in another embodiment.
  • Compounds of the invention may also be administered topically or enhanced by using a suitable topical transdermal vehicle or a transdermal patch.
  • the composition is preferably in the form of an ophthalmic composition.
  • the ophthalmic compositions are preferably formulated as eye-drop formulations and filled in appropriate containers to facilitate administration to the eye, for example a dropper fitted with a suitable pipette.
  • the compositions are sterile and aqueous based, using purified water.
  • an ophthalmic composition may contain one or more of: a) a surfactant such as a polyoxyethylene fatty acid ester; b) a thickening agents such as cellulose, cellulose derivatives, carboxyvinyl polymers, polyvinyl polymers, and polyvinylpyrrolidones, typically at a concentration n the range of about 0.05 to about 5.0% (wt/vol); c) (as an alternative to or in addition to storing the
  • the composition of this invention includes one or more additional agents.
  • the other therapeutic agent may be ay agent that is capable of treating, preventing or reducing the symptoms of a tetracycline-responsive disease or disorder.
  • the other therapeutic agent may be any agent of benefit to a patient when administered in combination with the tetracycline compound in this invention.
  • a suspension of CuCN (10.40 g, 115.90 mmol, 1.25 eq) in H 2 0 (44 mL) was mixed with a solution of NaCN (14.40 g, 294.80 mmol, 3.18 eq) in 22 mL of H 2 0 and cooled in an ice-bath.
  • the initial diazonium salt mixture was then added to the CuCN and NaCN mixture with vigorous stirring while maintaining the temperature at 0 °C (toluene (180 mL) was also added in portions during the addition).
  • the reaction mixture was stirred at 0 °C for 1 h, at rt for 2 h, and at 50 °C for another 1 h. After cooling to rt, the layers were separated.
  • the combined organic solution was extracted three times with 1 N aqueous NaOH.
  • the combined aqueous solution was acidified with 6 N aqueous HC1, and extracted three times with EtOAc.
  • the combined EtOAc extracts were washed with brine, dried over magnesium sulfate, and concentrated to provide 8.64 g of the benzoic acid intermediate as an off-white solid, which was used directly in the next step.
  • TrCl (5.75 g, 20.64 mmol, 1.2 eq) and TEA (3.12 mL, 22.36 mmol, 1.3 eq) were added to Sl-12 (17.2 mmol, crude, 1 eq) in CH 2 C1 2 (100 mL) at rt.
  • the reaction mixture was stirred at rt for 2 h and concentrated.
  • the residue was partitioned between EtOAc (300 mL) and water (100 mL). The organic phase was washed with water (50 mL x 2) and brine (50 mL), dried over MgS0 4 , and concentrated under reduced pressure to give the desired product Sl-13: MS (ESI) m/z 670.55 (M+H). This crude product was further dried by azeotroping several times from toluene and used in subsequent reactions without further purification.
  • n-BuLi (0.22 mL, 2.5 M/hexanes, 0.55 mmol, 2.2 eq) was added drop wise to a solution of diisopropylamine (81 ⁇ , 0.58 mmol, 2.3 eq) in THF (3 mL) at -78 °C.
  • the reaction solution was stirred at 0 °C for 5 min and cooled to -78 °C.
  • TMEDA (86 ⁇ , 0.58 mmol, 2.3 eq) was added.
  • the reaction solution was stirred at -78 °C for 10 min.
  • a solution of ester Sl-12 (107 mg, 0.25 mmol, 1 eq) in THF (1 mL) was added drop wise via a cannula.
  • the crude product was purified by preparative reverse phase HPLC on a Waters Autopurification system using a Sunfire Prep C 18 OBD column [5 ⁇ , 19 x 50 mm; flow rate, 20 mL/min; Solvent A: H 2 0 with 0.1% HC0 2 H; Solvent B: CH 3 CN with 0.1% HC0 2 H; injection volume: 4.0 mL
  • Aqueous HF 48-50%, 0.3 mL was added to a solution of the above intermediate in THF (0.6 mL) in a polypropylene reaction vessel at 23 °C. The mixture was stirred vigorously at 23 °C overnight and poured into aqueous K 2 HP0 4 (3.6 g dissolved in 30 mL water). The mixture was extracted with EtOAc (30 mL, 15 mL). The combined organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was used directly in the next step without further purification (MS (ESI) m/z 616.56 (M+H)).
  • reaction mixture was stirred at 0 °C for 25 min.
  • Saturated aqueous NaHC0 3 300 mL was added.
  • the reaction mixture was stirred for 20 min and extracted with dichloromethane (400 mL). The organic extract was dried over anhydrous sodium sulfate and concentrated.
  • reaction mixture was gradually warmed to 0 °C over 90 min, quenched with aqueous potassium phosphate buffer (pH 7.0) and saturated aqueous NH 4 C1, and extracted with EtOAc (50 mL). The organic extract was dried over Na 2 S0 4 and concentrated. The residue was purified by a preparative reverse phase HPLC on a Waters
  • Acetic acid 5.0 ⁇ , 0.090 mmol, 2 eq
  • sodium triacetoxyborohydride (19 mg, 0.090 mmol, 2 eq) were added sequentially to a solution of compound S2-5 (36 mg, 0.045 mmol, 1 eq) in 1 ,2-dichloroethane (1 mL) at 23 °C.
  • CH 3 CHO (12.7 ⁇ , 0.23 mmol, 5 eq) was added.
  • the crude product was purified by preparative reverse phase HPLC on a Waters Autopurification system using a Sunfire Prep C18 OBD column [5 ⁇ , 19 x 50 mm; flow rate, 20 mL/min; Solvent A: H 2 0 with 0.1% HC0 2 H; Solvent B: CH 3 CN with 0.1% HC0 2 H;
  • S3-7-2 was prepared from S3-4 by HF treatment and hydrogenation according to procedures used for S3-7-1: 1H NMR (400 MHz, CD 3 OD) ⁇ 6.99 (s, 1 H), 4.51-4.54 (m, 1 H), 4.12 (s, 1 H), 3.75 (s, 3 H), 3.46-3.49 (m, 1 H), 2.98-3.27 (m, 10 H), 2.36-2.44 (m, 1H), 2.25-2.28 (m, 1H), 1.80-2.50 (m, 6H), 1.62-1.71 (m, 1H); MS (ESI) m/z 528.1 (M+H).
  • reaction mixture was warmed to -10 °C gradually over 30 min, quenched with saturated aqueous NH 4 C1 (50 mL), and extracted with EtOAc (50 mL). The organic phase was separated, dried over Na 2 S0 4 , and concentrated to yield S4-6-1, which was used directly in the next step without further purification.
  • TMEDA (0.10 mL, 0.48 mmol, 1.3 eq) was added, followed by the drop wise addition of S5-1 (0.20 g, 0.37 mmol, 1 eq) in dry THF (1 mL) via a cannula. After complete addition, the resulting dark-red mixture was stirred for 1 h at -78 °C and cooled to -100 °C. A solution of enone S2-1 (0.18 g, 0.37 mmol, 1 eq) in THF (lmL) was added drop wise via a cannula. The resulting red mixture was slowly warmed to -78 °C.
  • PhB(OH) 2 (57 mg, 0.47 mmol, 2 eq)
  • Pd(PPh 3 ) 4 (8 mg, 0.007 mmol, 0.03 eq)
  • K 2 C0 3 65 mg, 0.47 mmol, 2 eq
  • HCHO (1.59 mL, 37% aqueous solution, 21.42 mmol, 6 eq)
  • HOAc (0.62 mL, 10.71 mmol, 3 eq)
  • Na(OAc) 3 BH (2.27 g, 10.71 mmol, 3 eq)
  • the reaction mixture was stirred at rt for 2 h.
  • Additional Na(OAc) 3 BH (0.38 g, 1.78 mmol, 0.5 eq) was added.
  • the reaction mixture was stirred at rt overnight.
  • Saturated aqueous NaHC0 3 70 mL was added slowly (bubbling).

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Abstract

La présente invention concerne un composé représenté par la formule structurelle (I), ou un sel pharmaceutiquement acceptable de celui-ci. Les variables de la formule structurelle (I) sont tels que définis dans la description. L'invention concerne également une composition pharmaceutique comportant le composé de formule structurelle (I) et son utilisation thérapeutique.
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US8501716B2 (en) 2008-08-08 2013-08-06 Tetraphase Pharmaceuticals, Inc. C7-fluoro substituted tetracycline compounds
WO2014036502A3 (fr) * 2012-08-31 2014-04-24 Tetraphase Pharmaceuticals, Inc. Composés de tétracyclines
US9315451B2 (en) 2009-05-08 2016-04-19 Tetraphase Pharmaceuticals, Inc. Tetracycline compounds
US9624166B2 (en) 2009-08-28 2017-04-18 Tetraphase Pharmaceuticals, Inc. Tetracycline compounds
WO2018026798A1 (fr) * 2016-08-01 2018-02-08 Aptinyx Inc. Modulateurs de nmda spiro-lactame et leurs procédés d'utilisation
WO2018045084A1 (fr) 2016-08-30 2018-03-08 Tetraphase Pharmaceuticals, Inc. Composés de tétracycline et méthodes de traitement
US9918998B2 (en) 2015-03-23 2018-03-20 BioPharmX, Inc. Pharmaceutical tetracycline composition for dermatological use
US10441571B2 (en) 2013-01-29 2019-10-15 Aptinyx Inc. Spiro-lactam NMDA receptor modulators and uses thereof
US10906913B2 (en) 2008-09-18 2021-02-02 Northwestern University NMDA receptor modulators and uses thereof
US10918637B2 (en) 2016-08-01 2021-02-16 Aptinyx Inc. Spiro-lactam NMDA receptor modulators and uses thereof
US10961190B2 (en) 2016-10-19 2021-03-30 Tetraphase Pharmaceuticals, Inc. Crystalline forms of eravacycline
US10961189B2 (en) 2016-08-01 2021-03-30 Aptinyx Inc. Spiro-lactam NMDA receptor modulators and uses thereof
US11028095B2 (en) 2016-08-01 2021-06-08 Aptinyx Inc. Spiro-lactam and bis-spiro-lactam NMDA receptor modulators and uses thereof
US11299495B2 (en) 2016-08-01 2022-04-12 Aptinyx Inc. Spiro-lactam NMDA receptor modulators and uses thereof
WO2023004918A1 (fr) * 2021-07-28 2023-02-02 深圳市真味生物科技有限公司 Méthode de préparation de nicotine chirale à partir de tert-butyl sulfinamide chiral
US11578072B2 (en) 2018-01-31 2023-02-14 Aptinyx Inc. Spiro-lactam NMDA receptor modulators and uses thereof

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US8501716B2 (en) 2008-08-08 2013-08-06 Tetraphase Pharmaceuticals, Inc. C7-fluoro substituted tetracycline compounds
US8796245B2 (en) 2008-08-08 2014-08-05 Tetraphase Pharmaceuticals, Inc. C7-fluoro substituted tetracycline compounds
US8906887B2 (en) 2008-08-08 2014-12-09 Tetraphase Pharmaceuticals, Inc. C7-fluoro substituted tetracycline compounds
US10906913B2 (en) 2008-09-18 2021-02-02 Northwestern University NMDA receptor modulators and uses thereof
US10072007B2 (en) 2009-05-08 2018-09-11 Tetraphase Pharmaceuticals, Inc. Tetracycline compounds
US9315451B2 (en) 2009-05-08 2016-04-19 Tetraphase Pharmaceuticals, Inc. Tetracycline compounds
US9624166B2 (en) 2009-08-28 2017-04-18 Tetraphase Pharmaceuticals, Inc. Tetracycline compounds
CN104768922B (zh) * 2012-08-31 2018-04-03 四相制药公司 四环素化合物
US10315992B2 (en) 2012-08-31 2019-06-11 Tetraphase Pharmaceuticals, Inc. Tetracyline compounds
KR102375238B1 (ko) 2012-08-31 2022-03-15 테트라페이즈 파마슈티컬스, 인코포레이티드 테트라사이클린 화합물
KR20210107184A (ko) * 2012-08-31 2021-08-31 테트라페이즈 파마슈티컬스, 인코포레이티드 테트라사이클린 화합물
KR102295673B1 (ko) * 2012-08-31 2021-08-27 테트라페이즈 파마슈티컬스, 인코포레이티드 테트라사이클린 화합물
US20200048193A1 (en) * 2012-08-31 2020-02-13 Tetraphase Pharmaceuticals, Inc. Tetracycline compounds
CN108276404A (zh) * 2012-08-31 2018-07-13 四相制药公司 四环素化合物
CN108329312A (zh) * 2012-08-31 2018-07-27 四相制药公司 四环素化合物
CN104768922A (zh) * 2012-08-31 2015-07-08 四相制药公司 四环素化合物
WO2014036502A3 (fr) * 2012-08-31 2014-04-24 Tetraphase Pharmaceuticals, Inc. Composés de tétracyclines
EA031523B1 (ru) * 2012-08-31 2019-01-31 Тетрафейз Фармасьютикалс, Инк. Тетрациклиновые соединения
EP3461809A1 (fr) * 2012-08-31 2019-04-03 Tetraphase Pharmaceuticals, Inc. Composés de tétracycline
US10913712B2 (en) 2012-08-31 2021-02-09 Tetraphase Pharmaceuticals, Inc. Tetracycline compounds
US9573895B2 (en) 2012-08-31 2017-02-21 Tetraphase Pharmaceuticals, Inc. Tetracycline compounds
KR20150065172A (ko) * 2012-08-31 2015-06-12 테트라페이즈 파마슈티컬스, 인코포레이티드 테트라사이클린 화합물
US11077094B2 (en) 2013-01-29 2021-08-03 Aptinyx Inc. Spiro-lactam NMDA receptor modulators and uses thereof
US10441571B2 (en) 2013-01-29 2019-10-15 Aptinyx Inc. Spiro-lactam NMDA receptor modulators and uses thereof
US10441572B2 (en) 2013-01-29 2019-10-15 Aptinyx Inc. Spiro-lactam NMDA receptor modulators and uses thereof
US10881672B2 (en) 2015-03-23 2021-01-05 BioPharmX, Inc. Pharmaceutical tetracycline composition for dermatological use
US9918998B2 (en) 2015-03-23 2018-03-20 BioPharmX, Inc. Pharmaceutical tetracycline composition for dermatological use
US10391108B2 (en) 2015-03-23 2019-08-27 BioPharmX, Inc. Pharmaceutical tetracycline composition for dermatological use
US11299495B2 (en) 2016-08-01 2022-04-12 Aptinyx Inc. Spiro-lactam NMDA receptor modulators and uses thereof
US11530223B2 (en) 2016-08-01 2022-12-20 Aptinyx Inc. Spiro-lactam NMDA receptor modulators and uses thereof
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US10961189B2 (en) 2016-08-01 2021-03-30 Aptinyx Inc. Spiro-lactam NMDA receptor modulators and uses thereof
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US11512051B2 (en) 2016-08-01 2022-11-29 Aptinyx Inc. Spiro-lactam NMDA receptor modulators and uses thereof
AU2017306164B2 (en) * 2016-08-01 2021-10-21 Aptinyx Inc. Spiro-lactam NMDA modulators and methods of using same
WO2018026798A1 (fr) * 2016-08-01 2018-02-08 Aptinyx Inc. Modulateurs de nmda spiro-lactame et leurs procédés d'utilisation
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IL264482B (en) * 2016-08-01 2022-09-01 Aptinyx Inc Spiro-lactam nmda modulators and methods of their use
US10918637B2 (en) 2016-08-01 2021-02-16 Aptinyx Inc. Spiro-lactam NMDA receptor modulators and uses thereof
US11427585B2 (en) 2016-08-01 2022-08-30 Aptinyx Inc. Spiro-lactam NMDA modulators and methods of using same
CN110167560B (zh) * 2016-08-30 2023-08-18 四相制药公司 四环素化合物和治疗方法
WO2018045084A1 (fr) 2016-08-30 2018-03-08 Tetraphase Pharmaceuticals, Inc. Composés de tétracycline et méthodes de traitement
JP7184756B2 (ja) 2016-08-30 2022-12-06 テトラフェース ファーマシューティカルズ，インコーポレイテッド テトラサイクリン化合物および処置方法
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JP7184756B6 (ja) 2016-08-30 2022-12-20 テトラフェース ファーマシューティカルズ，インコーポレイテッド テトラサイクリン化合物および処置方法
US20230031954A1 (en) * 2016-08-30 2023-02-02 Tetraphase Phamaceuticals, Inc. Tetracycline compounds and methods of treatment
JP2019532031A (ja) * 2016-08-30 2019-11-07 テトラフェース ファーマシューティカルズ，インコーポレイテッド テトラサイクリン化合物および処置方法
US10961190B2 (en) 2016-10-19 2021-03-30 Tetraphase Pharmaceuticals, Inc. Crystalline forms of eravacycline
US11578044B2 (en) 2016-10-19 2023-02-14 Tetraphase Pharmaceuticals, Inc. Crystalline forms of eravacycline
US11578072B2 (en) 2018-01-31 2023-02-14 Aptinyx Inc. Spiro-lactam NMDA receptor modulators and uses thereof
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